title: Phagocytosis executes delayed neuronal death after focal brain ischemia.
abstract: Delayed neuronal loss and brain atrophy after cerebral ischemia contribute to stroke and dementia pathology, but the mechanisms are poorly understood. Phagocytic removal of neurons is generally assumed to be beneficial and to occur only after neuronal death. However, we report herein that inhibition of phagocytosis can prevent delayed loss and death of functional neurons after transient brain ischemia. Two phagocytic proteins, Mer receptor tyrosine kinase (MerTK) and Milk fat globule EGF-like factor 8 (MFG-E8), were transiently up-regulated by macrophages/microglia after focal brain ischemia in vivo. Strikingly, deficiency in either protein completely prevented long-term functional motor deficits after cerebral ischemia and strongly reduced brain atrophy as a result of inhibiting phagocytosis of neurons. Correspondingly, in vitro glutamate-stressed neurons reversibly exposed the "eat-me" signal phosphatidylserine, leading to their phagocytosis by microglia; this neuronal loss was prevented in the absence of microglia and reduced if microglia were genetically deficient in MerTK or MFG-E8, both of which mediate phosphatidylserine-recognition. Thus, phagocytosis of viable neurons contributes to brain pathology and, surprisingly, blocking this process is strongly beneficial. Therefore, inhibition of specific phagocytic pathways may present therapeutic targets for preventing delayed neuronal loss after transient cerebral ischemia.
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, United Kingdom.
authors.forename: Jonas J
authors.initials: JJ
authors.lastname: Neher
authors.forename: Julius V
authors.initials: JV
authors.lastname: Emmrich
authors.forename: Michael
authors.initials: M
authors.lastname: Fricker
authors.forename: Palwinder K
authors.initials: PK
authors.lastname: Mander
authors.forename: Clotilde
authors.initials: C
authors.lastname: Théry
authors.forename: Guy C
authors.initials: GC
authors.lastname: Brown
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D001284:Atrophy; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D020520:Brain Infarction / Q000235:genetics / Q000378:metabolism; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D002478:Cells, Cultured; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D008894:Milk Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010587:Phagocytosis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011922:Rats, Mutant Strains; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation; D000076202:c-Mer Tyrosine Kinase
chemical_list: D000954:Antigens, Surface; D018836:Inflammation Mediators; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase
keywords: neuroinflammation; phagoptosis